Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité , Service de Rhumatologie A, Hôpital Cochin, Paris, France.
Ann Rheum Dis. 2017 Nov;76(11):1931-1940. doi: 10.1136/annrheumdis-2016-210821. Epub 2017 Aug 11.
To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH).
IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks.
IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF.
We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements.
评估全过氧化物酶体增殖物激活受体（PPAR）激动剂 IVA337 在肺纤维化和相关肺动脉高压（PH）的临床前小鼠模型中的抗纤维化作用。
IVA337 已在博来霉素诱导的肺纤维化小鼠模型和 Fra-2 转基因小鼠中进行了评估，后者表现为非特异性间质性肺炎和严重的肺血管重塑导致 PH。小鼠接受两次剂量的 IVA337（30mg/kg 或 100mg/kg）或载体，通过每日口服灌胃给药，持续 4 周。
IVA337 在 100mg/kg 剂量下，与接受 30mg/kg 的 IVA337 或载体的小鼠相比，在两种小鼠模型中均显著保护免受肺纤维化的发展。组织学评分在博莱霉素模型中降低了 61%，在 Fra-2 转基因小鼠中降低了 50%，与接受载体治疗的小鼠相比，总肺羟脯氨酸浓度分别降低了 28%和 48%。IVA337 在 100mg/kg 时还显著降低了两种小鼠模型病变肺中的纤维化标志物水平。此外，IVA337 通过改善血流动力学测量和血管重塑，显著减轻 Fra-2 转基因小鼠的 PH。在原代人肺成纤维细胞中，IVA337 以剂量依赖性方式抑制 TGF-β诱导的成纤维细胞向肌成纤维细胞的转化和 PDGF 介导的成纤维细胞增殖。
我们证明，100mg/kg 的 IVA337 治疗可预防两种互补动物模型中的肺纤维化，并显著减轻 Fra-2 小鼠模型中的 PH。这些发现证实，全过氧化物酶体增殖物激活受体激动剂 IVA337 是这些心肺受累的有吸引力的治疗候选药物。
